The invention relates to a pediatric formula, and particularly relates to enhancing the tolerance of pediatric patients fed the formula. Pediatric patients include both infants (children 12 months of age or less) and children (children more than 12 months of age but less than 13 yrs of age). (Therefore, all infants are children, but not all children will be infants.) More specifically, the invention is a pediatric formula comprising xanthan gum that has been found effective in increasing tolerance in patients fed such a formula. The invention is also a method of providing nutrition and a method of improving tolerance comprising administering an effective amount of a pediatric formula comprising xanthan gum.
Pediatric formulas may be classified into three general types based on the type of protein: intact protein-based, hydrolyzed protein-based, and free amino acid-based. (Pediatric formulas encompass infant formulas and formulas intended for children one year and older.) Commercial pediatric formulas may also contain, in addition to a protein source, carbohydrates, lipids, vitamins and minerals. Free amino acids are currently utilized as the pediatric source in pediatric formulas (EleCare(trademark), Ross Products Division of Abbott Laboratories) intended for children one year and older who have one or more of the following: problems digesting and absorbing regular foods, severe food allergies, gastrointestinal tract problems, or other conditions in which an elemental diet is needed.
Many pediatric patients experience intolerance to certain formulas (formula intolerance). The terms intolerance and formula intolerance are used interchangeably herein. Intolerance is a non-immune system associated reaction and may be evidenced by behavior or stool or feeding pattern changes such as increased spit-up or vomiting, an increased number of stools, more watery stools, and increased fussiness as compared to normal infants who tolerate formula well. Intolerance is most often indicated by gastrointestinal symptoms (e.g. emesis, stool patterns and gas) as well as behavioral characteristics (e.g. acceptance of formula, fussing and crying). In clinical study settings such behavior may be cause for parents to remove their infants from a particular study. Infants removed from a study because of such behaviors are referred to as exits for intolerance. In a non-clinical setting such behavior often causes parents to switch formulas.
Intolerance can be contrasted with the allergic-type reactions some infants exhibit to certain formulas. These allergic-type reactions are immune system associated, and may be caused by the infant""s sensitivity to the protein present in the formula. Many infants who exhibit allergies or sensitivities to intact (whole) proteins, such as those in intact cow""s milk protein or intact soy protein isolate-based formulas, are able to tolerate extensively hydrolyzed protein. (Hydrolysate formulas (also referred to as semi-elemental formulas) contain protein that has been hydrolyzed or broken down into short peptide fragments and amino acids and as a result is more easily digested by all infants.) These immune system associated allergies or sensitivities often result in cutaneous, respiratory or gastrointestinal symptoms such as vomiting and diarrhea. Infants who exhibit reactions to intact protein formulas often will not react to hydrolysate formulas because their immune system does not recognize the hydrolyzed protein as the intact protein that causes their symptoms. Infants who exhibit immune system associated reactions to formulas may also exhibit non-immune system associated reactions (formula intolerance), as previously described.
Many different pediatric formulas are in existence. Much of the previous focus in the art has been on the physical stability of the formulas, and concurrent processing or manufacturing concerns.
U.S. Pat. No. 5,192,577 to Masson discloses and teaches the use of xanthan gum in a nutritional formula but only as a stabilizer and specifically limits that use to formulas that use kappa carrageenan in combination with the xanthan gum. Masson deals primarily with the physical stability of the nutritional formula disclosed therein and does not address the problem of intolerance exhibited by patients fed the formula.
U.S. Pat. No. 5,472,952 to Smidt et al. relates to nutritionally complete food compositions which contain partially hydrolyzed pectin for the management of diarrhea. The use of xanthan gum as an emulsifier or stabilizer is disclosed but no teaching of the amount of xanthan gum is provided.
U.S. Pat. No. 5,681,600 to Anfinone et al. discloses use of xanthan gum in a nutritional formula but teaches that such use of xanthan gum is unacceptable because of unacceptable calcium delivery resulting from use of formulas comprising xanthan gum.
U.S. Pat. No. 4,670,268 to Mahmoud discloses an enteral nutritional hypoallergenic nutritional formula which may contain xanthan gum as a stabilizer but fails to provide any teaching of effective amounts of xanthan gum for that purpose.
U.S. Pat. No. 5,919,512 to Montezinos discloses the use of xanthan gum as a stabilizer in a flavoricloud emulsion such as is present in dilute juice and tea beverages. The emulsion disclosed therein contains no protein and thus, would be unsatisfactory for use as a pediatric formula.
U.S. Pat. No. 5,597,595 to DeWille et al. discloses the use of xanthan gum as an emulsion stabilizer in a low pH beverage fortified with calcium and vitamin D.
U.S. Pat. No. 5,817,351 to DeWille et al. discloses the use of xanthan gum as a stabilizer in low pH beverages that are calcium fortified. The beverages disclosed therein contain no fat and protein and would be unsuitable as a complete nutritional source.
U.S. Pat. No. 5,609,897 to Chandler et al. discloses the use of xanthan gum in a soft drink like powdered beverage that has been fortified with calcium and vitamin D.
U.S. Pat. No. 5,858,449 to Crank et al. discloses the use of xanthan gum in an isoflavone-enriched soy-based frozen dessert.
In general, the prior art nutritional formulas completely fail to address the problem of intolerance. Thus, there is an unmet need for a formula that is more readily tolerated by pediatric patients who exhibit symptoms of intolerance. A formula that is better tolerated will result in behavior more similar to that displayed by normal pediatric patients who tolerate formula well.
The present invention provides an improved pediatric formula and methods for providing nutrition and increasing the tolerance of children fed the formula. (As used herein, unless otherwise indicated, the term children is meant to encompass both infants and children over one year in age. The terms child/children and pediatric patient are also used interchangeably.) The use of xanthan gum has provided unexpected improvements in tolerance. The formula may be in liquid concentrate, ready-to-feed or powdered form. The formula comprises, based on a 100 kcal basis, about 8 to about 16 grams carbohydrate (preferably about 9.4 to about 12.3 grams), about 3 to about 6 grams lipid (preferably about 4.7 to about 5.6 grams), about 1.8 to about 3.3 grams protein (preferably about 2.4 to about 3.3 grams), and a tolerance improver comprising about 37 to about 370 milligrams (preferably about 74 to about 222 milligrams, more preferably about 111 to about 148 milligrams) xanthan gum. If the formula is provided in a powder form, it comprises based on 100 grams of powder, about 30 to about 90 grams carbohydrate (preferably about 48 to about 59 grams), about 15 to about 30 grams lipid (preferably about 20 to about 30), about 8 to about 17 grams protein (preferably about 10 to about 17 grams), and about 188 to about 1880 milligrams (preferably about 375 to about 1125 milligrams, more preferably about 565 to about 750 milligrams) xanthan gum.
The formula may further comprise a stabilizer and also preferably comprises vitamins and minerals in amounts sufficient to supply the daily nutritional requirements of infants or children over one. When the formula is an infant formula, the amounts of vitamins and minerals are preferably selected according to FDA guidelines. When infants are fed a formula according to the invention, improved tolerance is exhibited by those infants, as compared to infants fed a formula with the same composition but lacking the tolerance improver.
The invention also provides methods of providing nutrition to and improving tolerance in a pediatric patient. The methods comprise feeding the child an effective amount of a formula comprising, based on a 100 kcal basis, about 8 to about 16 grams carbohydrate (preferably about 9.4 to about 12.3 grams), about 3 to about 6 grams lipid (preferably about 4.7 to about 5.6 grams), about 1.8 to about 3.3 grams protein (preferably about 2.4 to about 3.3 grams), and a tolerance improver comprising about 37 to about 370 milligrams (preferably about 74 to about 222 milligrams, more preferably about 111 to about 148 milligrams) xanthan gum. If the formula is provided in a powder form, it comprises based on 100 grams of powder, about 30 to about 90 grams carbohydrate (preferably about 48 to about 59 grams ), about 15 to about 30 grams lipid (preferably about 22 to about 28), about 8 to about 17 grams protein (preferably about 11 to about 17 grams), and about 188 to about 1880 milligrams (preferably about 375 to about 1125 milligrams, more preferably about 565 to about 750 milligrams) xanthan gum. Children fed formulas of the invention exhibit fewer symptoms of intolerance than children fed the same formula but lacking the xanthan gum tolerance improver.
The present invention provides an improved pediatric formula that reduces the intolerance of children fed the formula. The invention also provides methods for providing nutrition to and improving tolerance in pediatric patients comprising feeding a formula of the invention. The use of xanthan gum has provided unexpected improvements in tolerance.
Intolerance (formula intolerance) in infants is often indicated by gastrointestinal symptoms (e.g. emesis, stool pattems, and gas) as well as behavioral characteristics (e.g. acceptance of formula, fussing, and crying). For purposes of this invention, improved tolerance (or reduced intolerance) is defined as an improvement (change towards normal patterns) of one or more of the following symptoms or characteristics: stool pattern, vomiting, spit up, acceptance of formula, fussing, crying, or exits for intolerance (clinical setting).
The pediatric formula of the invention may be provided in powdered, liquid concentrate or ready-to-feed forms. Before feeding, water is added to both the powdered and concentrate forms of the formula. In a first embodiment, a pediatric formula of the invention comprises, based on a 100 kcal basis, about 8 to about 16 grams carbohydrate (preferably about 9.4 to about 12.3 grams), about 3 to about 6 grams lipid (preferably about 4.7 to about 5.6 grams), about 1.8 to about 3.3 grams protein (preferably about 2.4 to about 3.3 grams), and a tolerance improver comprising about 37 to about 370 milligrams (preferably about 74 to about 222 milligrams, more preferably about 111 to about 148 milligrams) xanthan gum. If provided in a powder form, the formula comprises, based on 100 grams of powder, about 30 to about 90 grams carbohydrate (preferably about 48 to about 59 grams ), about 15 to about 30 grams lipid (preferably about 22 to about 28), about 8 to about 17 grams protein (preferably about 11 to about 17 grams), and about 188 to about 1880 milligrams (preferably about 375 to about 1125 milligrams, more preferably about 565 to about 750 milligrams) xanthan gum. A summary of the carbohydrate, lipid and protein ranges (on a per 100 kcal basis, per 100 grams powder basis and per liter basis (as fed concentration) for a formula according to the invention is provided in Table I.
Xanthan gum is a high molecular weight polysaccharide produced by fermentation of a carbohydrate by Xanthomonas campestris. While xanthan gum is available in various mesh sizes, the use of xanthan gum in this invention is not limited to any particular mesh size. An appropriate mesh size may be selected based on processing parameters, e.q., a finer mesh size (200 mesh) may be preferred if the xanthan gum is to be dry blended into a formula whereas, a more coarse size (80 mesh) may be preferred if the xanthan gum is not dry blended into a formula. A suitable xanthan gum for use in this invention is Keltrol_F Xanthan Gum (200 mesh) available from Kelco, a division of Monsanto, Chicago, Ill.
Suitable carbohydrates, lipids and proteins can vary widely and are well known to those skilled in the art of making pediatric formulas. Suitable carbohydrates may thus include, but are not limited to, hydrolyzed, intact, naturally and/or chemically modified starches sourced from corn, tapioca, rice or potato in waxy or non waxy forms; and sugars such as glucose, fructose, lactose, sucrose, maltose, high fructose corn syrup, and mixtures thereof. Maltodextrins are polysaccharides obtained from the acid or enzyme hydrolysis of starches such as those from corn or rice. Their classification is based on the degree of hydrolysis and is reported as dextrose equivalent (DE). When protein hydrolysates are the protein source, the DE of any maltodextrin utilized is preferably less than about 18-20. When protein hydrolysates are the protein source it is also preferable to avoid conditions which could lead to the formation of excessive Maillard browning products.
Suitable lipids include, but are not limited to, coconut oil, soy oil, corn oil, olive oil, safflower oil, high oleic safflower oil, MCT oil (medium chain triglycerides), sunflower oil, high oleic sunflower oil, palm oil, palm olein, canola oil, lipid sources of arachidonic acid and docosahexaneoic acid, and mixtures thereof. Lipid sources of arachidonic acid and docosahexaneoic acid include, but are not limited to, marine oil, egg yolk oil, and fungal oil.
Suitable protein sources include milk, soy, rice, meat (e.g., beef), animal and vegetable (e.g., pea, potato), egg (egg albumen), gelatin, and fish. Suitable intact proteins include, but are not limited to, soy based, milk based, casein protein, whey protein, rice protein, beef collagen, pea protein, potato protein and mixtures thereof. Suitable protein hydrolysates also include, but are not limited to, soy protein hydrolysate, casein protein hydrolysate, whey protein hydrolysate, rice protein hydrolysate, potato protein hydrolysate, fish protein hydrolysate, egg albumen hydrolysate, gelatin protein hydrolysate, a combination of animal and vegetable protein hydrolysates, and mixtures thereof. Hydrolyzed proteins (protein hydrolysates) are proteins that have been hydrolyzed or broken down into shorter peptide fragments and amino acids. Such hydrolyzed peptide fragments and free amino acids are more easily digested. In the broadest sense, a protein has been hydrolyzed when one or more amide bonds have been broken. Breaking of amide bonds may occur unintentionally or incidentally during manufacture, for example due to heating or shear. For purposes of this invention, the term hydrolyzed protein means a protein which has been processed or treated in a manner intended to break amide bonds. Intentional hydrolysis may be effected, for example, by treating an intact protein with enzymes or acids. The hydrolyzed proteins that are preferably utilized in formulas according to this invention are hydrolyzed to such an extent that the ratio of the amino nitrogen (AN) to total nitrogen (TN) ranges from about 0.1 AN to 1.0 TN to about 0.4 AN to about 1.0 TN, preferably about 0.25 AN to 1.0 TN to about 0.4 AN to about 1.0 TN. (AN:TN ratios given are for the hydrolysate protein source alone, and do not represent the AN:TN ratio in the final pediatric nutritional formula product, since free amino acids may be added as a supplement and would alter the reported value.) Protein may also be provided in the form of free amino acids. A formula according to the invention is preferably supplemented with various free amino acids in order to provide a more nutritionally complete and balanced formula. Examples of suitable free amino acids include, but are not limited to, tryptophan, tyrosine, cystine, taurine, L-methionine, L-arginine, and carnitine.
A formula of the invention preferably also contains vitamins and minerals in an amount designed to supply the daily nutritional requirements of a pediatric patient. The formula preferably includes, but is not limited to, the following vitamins and minerals: calcium, phosphorus, sodium, chloride, magnesium, manganese, iron, copper, zinc, selenium, iodine, and Vitamins A, E, C, D, K and the B complex. Further nutritional guidelines for infant formulas can be found in the Infant Formula Act, 21 U.S.C. section 350(a). The nutritional guidelines found in the Infant Formula Act continue to be refined as further research concerning infant nutritional requirements is completed. This invention is intended to encompass formulas containing vitamins and minerals that may not currently be listed in the Act.
In a second embodiment of the invention, the invention formula further comprises a stabilizer. Suitable stabilizers for use in pediatric nutritional formulas are well known to those skilled in the art. Suitable stabilizers include, but are not limited to, gum arabic, gum ghatti, gum karaya, gum tragacanth, agar, furcellaran, guar gum, gellan gum, locust bean gum, pectin, low methoxyl pectin, gelatin, microcrystalline cellulose, CMC (sodium carboxymethylcellulose), methylcellulose hydroxypropyl methyl cellulose, hydroxypropyl cellulose, DATEM (diacetyl tartaric acid esters of mono- and diglycerides), dextran, carrageenans, and mixtures thereof. A formula according to the invention preferably is free of kappa carrageenan as a stabilizer, and most preferably is free of a carrageenan. A formula is defined as being free of kappa carrageenan if any carrageenan utilized is predominately in another form (iota or lambda). For purposes of this invention, free of kappa carrageenan or free of carrageenan means that no kappa carrageenan or carrageenan is added during manufacturing. The amount of stabilizers utilized will vary depending upon the stabilizer(s) selected, the other ingredients present, and the stability and viscosity of the formula that is sought. Appropriate amounts can be determined by those of skill in the art based on the particular characteristics (e.g., viscosity) being sought in the formula.
The invention also provides methods of providing nutrition to and improving tolerance in a pediatric patient. The methods comprise feeding the child an effective amount of a formula comprising, based on a 100 kcal basis, about 8 to about 16 grams carbohydrate (preferably about 9.4 to about 12.3 grams), about 3 to about 6 grams lipid (preferably about 4.7 to about 5.6 grams), about 1.8 to about 3.3 grams protein (preferably about 2.4 to about 3.3 grams), and a tolerance improver comprising about 37 to about 370 milligrams (preferably about 74 to about 222 milligrams, more preferably about 111 to about 148 milligrams) xanthan gum. If the formula is provided in a powder form, it comprises based on 100 grams of powder, about 30 to about 90 grams carbohydrate (preferably about 48 to about 59 grams ), about 15 to about 30 grams fat (preferably about 22 to about 28), about 8 to about 17 grams protein (preferably about 11 to about 17 grams), and about 188 to about 1880 milligrams (preferably about 375 to about 1125 milligrams, more preferably about 565 to about 750 milligrams) xanthan gum.
In another embodiment, the formula may further comprise a stabilizer. Either embodiment also preferably comprises vitamins and minerals, in amounts as discussed above. Suitable carbohydrates, lipids, proteins or proteins, and stabilizers are well known to those skilled in the art and may include, but are not limited to, the substances described above. Preferably, if the formula is an infant formula, the method comprises feeding a sufficient amount of the formula to fulfill all of the infant""s daily nutritional requirements.
The pediatric formulas of this invention can be manufactured using techniques well known to those skilled in the art. Various processing techniques exist for producing powdered, ready-to-feed and concentrate liquid formulas. Typically, these techniques include formation of a slurry from one or more solutions which may contain water and one or more of the following: carbohydrates, proteins, lipids, stabilizers, vitamins and minerals. This slurry is emulsified, homogenized and cooled. Various other solutions may be added to the slurry before processing, after processing or at both times. The processed formula is then sterilized and may be diluted to be utilized on a ready-to-feed basis or stored in a concentrated liquid or a powder. If the resulting formula is meant to be a ready-to-feed liquid or concentrated liquid, an appropriate amount of water would be added before sterilization. If the resulting formula is meant to be a powder, the slurry will be heated and dried to obtain a powder. The powder resulting from drying may be dry blended with further ingredients, if desired.
The following examples are illustrative of the methods and compositions of the invention for improving tolerance in pediatric patients. While the invention is described in terms of a powdered infant nutritional formula in the examples, below, it is not intended to be so limited, as it is intended to encompass both ready-to-feed and concentrate liquid infant formulas as well as formulas for children one year in age or older. The examples are not intended to be limiting as other carbohydrates, lipids, proteins, stabilizers, vitamins and minerals may be used without departing from the scope of the invention.